Home LiteratureArticle Details
PMID: 17548474 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress.

Molecular and cellular biology ·Vol. 27 ·No. 15 ·2007-08-00 ·Pages 5499-513

Rahmani M, Davis EM, Crabtree TR, Habibi JR, Nguyen TK, Dent P, Grant S

Abstract

Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1alpha markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1alpha or XBP1, disruption of PERK activity, or inhibition of eIF2alpha phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.

MeSH Terms
Animals Benzenesulfonates/pharmacology Calcium Signaling/drug effects Caspase 2/metabolism Caspases, Initiator/metabolism Cell Death/drug effects Cell Line, Tumor DNA-Binding Proteins/metabolism Dose-Response Relationship, Drug Endoplasmic Reticulum/drug effects,pathology Endoplasmic Reticulum Chaperone BiP Enzyme Activation/drug effects Enzyme Induction/drug effects Eukaryotic Initiation Factor-2/metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Humans Mice Mitogen-Activated Protein Kinase Kinases/metabolism Niacinamide/analogs & derivatives Nuclear Proteins/metabolism Phenylurea Compounds Phosphorylation/drug effects Protein Biosynthesis/drug effects Protein Folding Protein Kinase Inhibitors/pharmacology Pyridines/pharmacology RNA Splicing/drug effects Reactive Oxygen Species/metabolism Regulatory Factor X Transcription Factors Sorafenib Transcription Factors X-Box Binding Protein 1 eIF-2 Kinase/antagonists & inhibitors,metabolism
Chemicals
Benzenesulfonates DNA-Binding Proteins Endoplasmic Reticulum Chaperone BiP Eukaryotic Initiation Factor-2 HSPA5 protein, human Hspa5 protein, mouse Nuclear Proteins Phenylurea Compounds Protein Kinase Inhibitors Pyridines Reactive Oxygen Species Regulatory Factor X Transcription Factors Transcription Factors X-Box Binding Protein 1 XBP1 protein, human Xbp1 protein, mouse Niacinamide Sorafenib PERK kinase eIF-2 Kinase Extracellular Signal-Regulated MAP Kinases Mitogen-Activated Protein Kinase Kinases CASP4 protein, human Caspase 2 Caspases, Initiator
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rahmani Mohamed
Department of Medicine, Division of Hematology/Oncology, MCV Station Box 230, Virginia Commonwealth University, Richmond, VA 23298, USA.
Davis Eric Maynard
Crabtree Timothy Ryan
Habibi Joseph Reza
Nguyen Tri K
Dent Paul
Grant Steven
References (69)
69 references, click to expand
  1. Kinase inhibition with BAY 43-9006 in renal cell carcinoma.
    Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S PMID: 15448036
  2. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.
    Cancer Res. 2004 Oct 1;64(19):7099-109 PMID: 15466206
  3. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells.
    Mol Cell Biol. 2004 Nov;24(22):9695-704 PMID: 15509775
  4. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516-20 PMID: 7682708
  5. Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins.
    J Biol Chem. 1997 Feb 14;272(7):4327-34 PMID: 9020152
  6. Depletion of intracellular Ca2+ store itself may be a major factor in thapsigargin-induced ER stress and apoptosis in PC12 cells.
    Neurochem Int. 2006 Jun;48(8):696-702 PMID: 16481070
  7. Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma.
    Clin Genitourin Cancer. 2006 Mar;4(4):246-8 PMID: 16729906
  8. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.
    J Clin Oncol. 2006 Jun 1;24(16):2505-12 PMID: 16636341
  9. Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs.
    Exp Cell Res. 2006 Jul 15;312(12):2347-57 PMID: 16701639
  10. The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway.
    J Biol Chem. 2006 Nov 3;281(44):33078-86 PMID: 16945918
  11. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.
    Nature. 2004 Aug 5;430(7000):694-9 PMID: 15258597
  12. Caspase inhibitors.
    Cell Death Differ. 1999 Nov;6(11):1081-6 PMID: 10578177
  13. Perk is essential for translational regulation and cell survival during the unfolded protein response.
    Mol Cell. 2000 May;5(5):897-904 PMID: 10882126
  14. BCL-2 family: regulators of cell death.
    Annu Rev Immunol. 1998;16:395-419 PMID: 9597135
  15. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.
    Nature. 1999 Jan 21;397(6716):271-4 PMID: 9930704
  16. Regulation of cap-dependent translation by eIF4E inhibitory proteins.
    Nature. 2005 Feb 3;433(7025):477-80 PMID: 15690031
  17. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors.
    Cancer Res. 2005 Mar 15;65(6):2412-21 PMID: 15781657
  18. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species.
    Cancer Res. 2005 Mar 15;65(6):2422-32 PMID: 15781658
  19. Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition.
    J Biol Chem. 2005 Apr 8;280(14):14189-202 PMID: 15684420
  20. Caspases-2, -3, and -7 are involved in thapsigargin-induced apoptosis of SH-SY5Y neuroblastoma cells.
    J Neurosci Res. 2005 May 15;80(4):576-83 PMID: 15825194
  21. The eukaryotic initiation factor 4E-binding proteins and apoptosis.
    Cell Death Differ. 2005 Jun;12(6):541-6 PMID: 15818413
  22. Involvement of GADD153 and cardiac ankyrin repeat protein in hypoxia-induced apoptosis of H9c2 cells.
    J Biol Chem. 2005 Jun 17;280(24):23122-9 PMID: 15826945
  23. Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation.
    J Biol Chem. 2005 Jun 17;280(24):23194-202 PMID: 15849362
  24. Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest.
    Cancer Res. 2005 Aug 1;65(15):6780-8 PMID: 16061660
  25. Endoplasmic reticulum stress: cell life and death decisions.
    J Clin Invest. 2005 Oct;115(10):2656-64 PMID: 16200199
  26. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation.
    J Biol Chem. 2005 Oct 21;280(42):35217-27 PMID: 16109713
  27. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006.
    Oncogene. 2005 Oct 20;24(46):6861-9 PMID: 16007148
  28. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway.
    Mol Biol Cell. 2005 Dec;16(12):5493-501 PMID: 16176978
  29. OSW-1: a natural compound with potent anticancer activity and a novel mechanism of action.
    J Natl Cancer Inst. 2005 Dec 7;97(23):1781-5 PMID: 16333034
  30. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells.
    Cancer Res. 2005 Dec 15;65(24):11510-9 PMID: 16357160
  31. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells.
    Cancer Res. 2006 Feb 1;66(3):1611-9 PMID: 16452220
  32. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells.
    Cancer Res. 2006 Feb 1;66(3):1702-11 PMID: 16452230
  33. From acute ER stress to physiological roles of the Unfolded Protein Response.
    Cell Death Differ. 2006 Mar;13(3):374-84 PMID: 16397578
  34. Cellular response to endoplasmic reticulum stress: a matter of life or death.
    Cell Death Differ. 2006 Mar;13(3):363-73 PMID: 16397583
  35. BAY 43-9006 inhibition of oncogenic RET mutants.
    J Natl Cancer Inst. 2006 Mar 1;98(5):326-34 PMID: 16507829
  36. PS-341 (bortezomib) induces lysosomal cathepsin B release and a caspase-2-dependent mitochondrial permeabilization and apoptosis in human pancreatic cancer cells.
    J Biol Chem. 2006 Apr 28;281(17):11923-32 PMID: 16446371
  37. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.
    Science. 2006 Apr 28;312(5773):572-6 PMID: 16645094
  38. Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells.
    Blood. 2000 Sep 1;96(5):1756-63 PMID: 10961874
  39. PERK mediates cell-cycle exit during the mammalian unfolded protein response.
    Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12625-30 PMID: 11035797
  40. Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells.
    Cancer Res. 2001 Jul 1;61(13):5106-15 PMID: 11431348
  41. Translational control is required for the unfolded protein response and in vivo glucose homeostasis.
    Mol Cell. 2001 Jun;7(6):1165-76 PMID: 11430820
  42. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.
    Cell. 2001 Dec 28;107(7):881-91 PMID: 11779464
  43. Regulated translation initiation controls stress-induced gene expression in mammalian cells.
    Mol Cell. 2000 Nov;6(5):1099-108 PMID: 11106749
  44. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.
    Nature. 2002 Jan 3;415(6867):92-6 PMID: 11780124
  45. Regulation of the endoplasmic reticulum calcium storage during the unfolded protein response--significance in tissue ischemia?
    Trends Cardiovasc Med. 2002 Feb;12(2):57-62 PMID: 11852251
  46. Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum.
    J Biol Chem. 2002 May 17;277(20):18077-83 PMID: 11877419
  47. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.
    Genes Dev. 2002 Jun 1;16(11):1345-55 PMID: 12050113
  48. The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apoptosis in human myeloid leukemia cells through a tumor necrosis factor-alpha-mediated process.
    Exp Cell Res. 2002 Jul 1;277(1):31-47 PMID: 12061815
  49. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells.
    Blood. 2002 Jul 1;100(1):194-9 PMID: 12070027
  50. Mutations of the BRAF gene in human cancer.
    Nature. 2002 Jun 27;417(6892):949-54 PMID: 12068308
  51. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.
    Nature. 2002 Aug 29;418(6901):934 PMID: 12198537
  52. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha.
    Mol Cell Biol. 2002 Nov;22(21):7405-16 PMID: 12370288
  53. Translational control in the endoplasmic reticulum stress response.
    J Clin Invest. 2002 Nov;110(10):1383-8 PMID: 12438433
  54. High frequency of BRAF mutations in nevi.
    Nat Genet. 2003 Jan;33(1):19-20 PMID: 12447372
  55. Stress-induced gene expression requires programmed recovery from translational repression.
    EMBO J. 2003 Mar 3;22(5):1180-7 PMID: 12606582
  56. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.
    J Natl Cancer Inst. 2003 Mar 19;95(6):484-6 PMID: 12644542
  57. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation.
    Genes Dev. 2003 Jun 15;17(12):1475-86 PMID: 12783855
  58. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice.
    FASEB J. 2003 Aug;17(11):1573-5 PMID: 12824288
  59. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition.
    Oncogene. 2003 Sep 18;22(40):6231-42 PMID: 13679862
  60. Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2.
    EMBO J. 2004 Jan 14;23(1):169-79 PMID: 14713949
  61. A trip to the ER: coping with stress.
    Trends Cell Biol. 2004 Jan;14(1):20-8 PMID: 14729177
  62. Defects in translational regulation mediated by the alpha subunit of eukaryotic initiation factor 2 inhibit antiviral activity and facilitate the malignant transformation of human fibroblasts.
    Mol Cell Biol. 2004 Mar;24(5):2025-40 PMID: 14966282
  63. Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process.
    Oncogene. 2004 Feb 19;23(7):1364-76 PMID: 14647418
  64. Redox and oxidant-mediated regulation of apoptosis signaling pathways: immuno-pharmaco-redox conception of oxidative siege versus cell death commitment.
    Int Immunopharmacol. 2004 Apr;4(4):475-93 PMID: 15099526
  65. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.
    J Cell Biol. 2004 May 10;165(3):347-56 PMID: 15123740
  66. A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2.
    J Biol Chem. 2004 Aug 13;279(33):34227-39 PMID: 15175350
  67. B-RAF is a therapeutic target in melanoma.
    Oncogene. 2004 Aug 19;23(37):6292-8 PMID: 15208680
  68. Calcium, ATP, and ROS: a mitochondrial love-hate triangle.
    Am J Physiol Cell Physiol. 2004 Oct;287(4):C817-33 PMID: 15355853
  69. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramideand etoposide-induced apoptosis.
    J Biol Chem. 2004 Sep 24;279(39):40755-61 PMID: 15262979
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.01080-06
Published
2007-08-00
Epub
2007-00-04
Pages
5499-513
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1952105
Subset
IM
Grants
NCI NIH HHS · R01 CA100866 · United States
NCI NIH HHS · R01 CA063753 · United States
NCI NIH HHS · R01 CA093738 · United States
NCI NIH HHS · CA 63753 · United States
NCI NIH HHS · CA 100866 · United States
NCI NIH HHS · CA 93738 · United States
External Links
PubMed source DOI: 10.1128/MCB.01080-06 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2